Cardiac arrest occurs when there is electrical or mechanical dysfunction in the heart, and results in the heart failing to pump blood, causing a lack of oxygen to the brain. There are many contributing factors, and include hypertension, diabetes, obesity, aging and drug use. Cardiac arrest results in death if not treated immediately; survival depends on timely defibrillation and administration of proper medications. Mortality is higher if treatment is delayed, but the prognosis is significantly improved if vigorous treatment begins immediately. Thus far drug therapies have had little effect on the mortality rate due to cardiac arrest. The primary goal during the past three decades has been to teach cardiopulmonary resuscitation (CPR) techniques to as many people as possible including BLS and ACLS in an attempt to increase the percent of survivors.
The anatomy of the heart is described and illustrated in detail in numerous reference works on anatomy and cardiac surgery, including standard texts such as Surgery of the Chest (Sabiston and Spencer, eds., Saunders Publ., Philadelphia). Basically, the heart has a special system of muscles that cause the heart tissue to regularly and continuously contract. It has two major pumping chambers, the left and right ventricles. Simultaneously contracting, these chambers expel blood into the aorta and the pulmonary artery. Blood enters the ventricles from the left and right atria, respectively. The atria are small antechambers that contract in a separate action preceding the major ventricular contraction by an interval of about 100 milliseconds (ms), known as the atrioventricular (AV) delay. The contractions arise from a wave of electrical excitation or depolarization waves that begin in the right atrium and spread to the left atrium. The excitation then enters the atrioventricular node delaying its passage into the ventricles via the bundle of His. The heart tissue contracts following its depolarization. The bundle of His regulates the speed of depolarization from the atria to the ventricles and insures that all muscle tissue surrounding a specific compartment simultaneously contracts and that the atria and ventricles contract in the proper time sequence. One complete contraction of both the ventricles and the atria constitutes a beat.
In patients with heart problems, the depolarization carried through the heart tissue may become irregular or chaotic (fibrillation), causing the heart to beat unevenly or to stop beating causing severe injuries or death. Detection and monitoring of heart problems is based on the appearance in an electrocardiogram of a small signal known as the P-wave accompanying atrial contraction with a much larger signal, known as the QRS complex, with a predominant R-wave, accompanying ventricular contraction. The P and R waves can be reliably detected as timing signals by electrical leads in contact with the respective heart chambers.
Current treatment for EMD consists of: 0.5-1 mg epinephrine IV with sodium bicarbonate; for asystole: 0.5-1 mg IV epinephrine and 1 mg atropine IV and sodium bicarbonate; no obtainable pulse: repeated defibrillation, 0.5-1 mg epinephrine, 1 mg/kg lidocaine and 5 mg/kg IV bretylium. American Heart Association (1986) JAMA 255:2905-2984. Despite current protocols, the rate of successful resuscitation has remained extremely poor Eisenberg et al. (1990) success with EMD has been reported at 0%, and asystole at less than 5%.
In view of the above, the dosage of epinephrine has been increased by fifteen fold. Parades et al. (1991) JAMA 265:1139-1144. The high dose adrenaline has not substantially changed the previously cited results. Menegazzi et al. (1993) Ann. Emerg. Med. 22:235-239.
A cardiac arrest is generally accompanied or preceded by severe pain in the left arm, jaw, neck or shoulders, although this is not always the case and some patients have little or no pain.
Treatment of cardiac arrest patients aims to relieve chest pain, stabilize the heart rhythm and preserve heart muscle tissue. Within 48 hours of successful alleviation of the cardiac arrest, the main problem is arrhythmia, which can be treated with antiarrhythmic drugs, or sometimes a pacemaker. To be most effective, thrombolytic therapy should be started within 6 hours of arrest: streptokinase, alteplase, urokinase and retoplase are used for this. For the treatment of the various complications that can set in, many options exist. Lidocaine is used for arrhythmias, atropine for bradycardia, morphine for general pain. There are drugs to increase myocardial contractility (blood pressure). Aspirin is used to inhibit platelet aggregation.
An ideal drug for use in treatment of cardiac arrest patients would act rapidly and directly to increase the effective mechanical contraction of the heart, decrease systemic vascular resistance and increase the heart rate. The effects of such a drug would be to increase survival of patients with sudden cardiac failure due to cardiac arrest.
Defibrillation
The revival of normal heart beat can be accomplished by a process called defibrillation which was developed and used over the past four decades. To defibrillate a heart, a large electrical charge called an electrical defibrillation pulse is applied to the heart. This electrical defibrillation pulse works to depolarize the heart muscle fibers, thus the heart may be restored to normal beating. Moreover, implantable defibrillators and arrhythmia controlling pacemakers, have also been developed and entered into wide clinical use.
The typical implantable defibrillator operates by supplying missing stimulation pulses on a pacing lead attached to the ventricle. The R-wave can be sensed by the same lead. An additional lead contacts the atrium to sense P-waves, if desired. In AV sequential pacers, discussed below, the atrial lead is also used for atrial stimulation.
Implantable defibrillators are useful in treating a number of cardiac disorders such as heart block caused by impairment of the ability of the bundle of His to conduct normal excitation from the atrium to the ventricle. The implantable defibrillator itself is a battery powered, hermetically sealed, completely self-contained electronic device which is implanted in the body at a suitable site such as the shoulder or axillary region within an inch from the surface of the skin. The distal ends of the leads are connected inside the heart to the right atrium and right ventricle and extend through a suitable blood vessel to the defibrillator. The proximal end of the lead is taken out through an opening in the blood vessel and electrically connected to the defibrillator. Inside the defibrillator, the stimulation pulses are formed by a pulse generator. In the past, pulse generators have taken several forms but fall into two general categories: (1) those where the pulse generator consists of an R-C timing circuit; and (2) those where oscillations in the output of a high frequency clock (R-C or crystal oscillator) are counted by digital circuitry. In circuits of the second kind, the pulse generator typically comprises a digital counter and logic circuitry for producing an output pulse when a given number of clock pulses is counted and means for resetting the counter in response to spontaneous or stimulated activity. An early example is found in U.S. Pat. No. 3,557,796.
With the miniaturization of stored program data processors, microprocessor cardiac defibrillation systems have given rise to more complex and yet more flexible counting arrangements. For example, a cardiac period number may be placed into a register that is regularly incremented and tested by software instructions. If the register has counted up to the programmed number, the software branches to direct the formation of a stimulation pulse, as in “Multi-Mode Microprocessor-Based Programmable Cardiac Pacer” U.S. patent application Ser. No. 207,003, filed Nov. 14, 1980 by Leckrone et al, assigned to the assignee of the present application.
The level of electrical stimulation is very important since the charge density in the myocardium surrounding the bare electrode at the distal end of the lead determines the muscular reaction. The electrical pulses for defibrillation and demand pacing are typically delivered to the heart through different methods. The defibrillation pulse from an implanted device has historically been delivered through a large area electrical patch sewn to the exterior surface of the heart. A second electrode may be placed inside the heart or elsewhere. The electrical patch and its counter-part are connected to a capacitor that is charged by a battery, to be capable of delivering an electrical defibrillation pulse between the contacts with tissues. Once the capacitor discharges the defibrillation pulse, the current enters directly into the heart of the subject so as to defibrillate the heart. The pulse then exits the body through the counter electrode.
Several factors are known to affect this charge density including the amplitude of the stimulation pulse current, the voltage, the duration of the stimulation or “pulse width”, the type of electrode including the area of contact and the resistance of the contacting tissue and electrochemical factors as well as the type of lead system used, i.e. unipolar or bipolar. In unipolar systems, the ground terminal is on the defibrillator itself while in bipolar systems the end of the lead contains two spaced contacts, one of which would be regarded as ground.
Advances in defibrillator development have enabled pulse parameters such as rate, width and amplitude to be altered by an externally generated programming signal, for example, using a succession of magnetic pulses to actuate a tiny reed switch in the defibrillator. In the past, the charge density delivered to the myocardium has been programmable by means of a variable voltage output circuit, a variable constant current output circuit, or a variable pulse width. Once a defibrillator is implanted and in operation at a selected pulse width and amplitude, it is extremely difficult at a later date for a physician not privy to the current parameter information, to ascertain the exact level of stimulation without knowing the amplitude beforehand. With defibrillators having fixed (i.e., known) amplitude and variable pulsewidth outputs, one can easily determine the applied stimulation level by gauging the pulsewidth. On the other hand, in providing for a wide range of stimulation levels in a single defibrillator, it has been found to be more effective to vary the amplitude. However, the stimulation level cannot then be easily determined by superficial electrical measurements.
The use of the demand pacer catheter makes it possible to apply demand pacing pulses to the heart. The demand pacer catheter is a long flexible probe, usually made of silastic or polyurethane, with electrical leads running the length of the catheter within. At one end of the probe, the leads are connected to an exposed metal surface called a demand pacer electrode. Part way up the probe, the leads are connected to a second exposed metal surface called a return electrode. Finally, at the other end of the probe, the leads are connected to a regulator that has a controller for sensing the beat of the heart and a pulse generator, for sending the demand pacer pulses to the heart when the heart would otherwise pause to contract.
The demand pacer catheter is used by making an incision in a vein leading to the heart. The end of the probe with the demand pacer electrode is inserted into the vein and threaded to the heart and into the right ventricle. When the heart muscle via the pacer electrode(s) delivers depolarization, the sensed signal is carried up the lead wires in the probe to the controller. If the electrode fails to deliver the signal from the heart, the controller senses the missing signal and trigger the pulse generator to transmit the electrical demand pacer pulse to the heart muscle via the demand pacer electrode. Once emitted from the electrode, the pulse stimulates the right ventricle, causing depolarization of the heart. The pulse current returns via the “ground” or return electrode.
The approaches for applying the different electrical pulses require two procedures, one for inserting the demand pacer catheter and one for attaching the defibrillator electrical patch, which expose the subject to high-risk conditions and a long recovery period. However, the high risk can be avoided by using a “lead” that can enter the heart via a vein to replace the patch.
Moreover, a single catheter can be inserted into the heart for applying both defibrillation and demand pacer pulses. This catheter can be an implantable, self-contained system for sensing the pulse of a heart and for automatically sending a defibrillator or demand pacer pulse to the heart depending on the condition of the heart.
Generally, the catheter for applying the defibrillation and demand pacer pulses has a flexible probe that can be inserted into a vein and threaded through the right atrium and into the right ventricle of the heart. A ground electrode and a demand pacer electrode are attached to the portion of the probe in the right ventricle. A defibrillator electrode is attached to the portion of the probe in the right atrium. Connected to the other end of the probe is a regulator having a controller for sensing and analyzing the electrical pulse of the heart. The regulator can further include a defibrillator capacitor and demand pacer capacitor for transmitting their respective pulses to the heart. The capacitor for defibrillation is charged by a battery located in the regulator. The regulator is inserted into the body, such as in the subcutaneous tissue of the chest wall, so that the system is independently contained within the body.
As the heart produces its electrical signal, the pulse is transferred through the probe and back to the controller. The controller then uses this information to determine if the heart is acting properly. If not, the controller automatically informs either the demand pacer capacitor or defibrillator capacitor to transmit its respective pulse to its respective electrode. The pulses then travel through the blood and into the surrounding heart tissue, thereby defibrillating or demand pacing the heart. Finally, the charge returns to the implanted controller via the return electrode.
U.S. Pat. No. 5,690,682 discusses a device for treating cardiac arrhythmia including an implantable programmable drug delivery system for injection of a pharmaceutical agent into the peritoneum. U.S. Pat. No. 5,527,344 discusses a pharmacologic atrial defibrillator and method for automatically delivering a defibrillating drug to a subject. Likewise, U.S. Pat. No. 5,220,917 discusses an implantable pharmacological defibrillator with automatic recognition of ventricular fibrillation.
However, the efficacy of these forms of therapy depends on many factors. Successful resuscitation is dependent on multiple medical armamentarium. Defibrillation terminates rapid uncoordinated heart muscle contraction. Many other critical problems can still occur after successful defibrillation. There may be a very slow heart rate (bradycardia), the beat may be erratic (arrhythmia) or there may be no heart rate (cardiac standstill). At times there may be an electrical impulse, yet no effective mechanical contraction (electromechanical dissociation—EMD); these conditions can cause damage to heart muscle tissue after the arrest has been successfully alleviated.
Although implantable defibrillators have increased survival of defibrillation, 50% of patients with implantable cadiovertor defibrillators still die. The exact etiology is unknown, but may be either asystole or pulseless electrical activity (PEA).
Despite the many advances in the development of new drugs and devices for treating subjects with cardiac arrest, these drugs and devices in the prior art have had little or no positive effect on the survival rate, which is still less than 10%. One reason for the low survival rate is that successful treatment depends upon determining the correct cause for abnormal cardiac contractions or lack of contractions.
Pulmonary Hypertension
Pulmonary hypertension is a progressive disease that occurs when pulmonary artery pressure rises above normal, for reasons other than the natural causes of aging or altitude. Primary pulmonary hypertension is rare, with no known cause, and occurring most often in females aged 20-40. Secondary hypertension occurs as a result of an existing condition such as cardiac or pulmonary disease, or use of certain drugs. The long-term prognosis for primary hypertension is poor; only 25% of patients survive for five years after diagnosis.
Within the body, blood flows through the pulmonary system (pulmonary circulation) and through the rest of the body (systemic circulation). Normally, the blood flow through both of these circulations is equal, although the resistance offered in the pulmonary circulation is generally much less than that offered in the systemic circulation. When resistance to pulmonary blood flow increases, the pressure in the pulmonary circulation is greater for any particular flow. This state is referred to as pulmonary hypertension.
Pulmonary hypertension begins when the medial and intimal muscle layers thicken, causing decreased distensibility and increased resistance. Cases of pulmonary hypertension are divided into two groups, designated primary and secondary. In most cases of pulmonary hypertension, there is an obvious cause for the increase in resistance to pulmonary blood flow, for example pulmonary emboli, malfunction of heart valves or muscle, or a mismatch between vascular capacity and essential blood flow, such as caused by congenital or acquired abnormalities or after surgery. For example, acquired cardiac diseases such as rheumatic valvular disease increase pulmonary arterial pressure by restricting blood flow from returning to the heart. These cases, where there is an obvious underlying cause of the hypertension, regardless of what that underlying cause is, are known as secondary pulmonary hypertension. Diagnosis of pulmonary hypertension can be difficult as there is no definitive set of values that can be used to establish the presence of hypertension.
In industrialized countries, chronic obstructive pulmonary disease accounts for the vast majority of cases of secondary pulmonary hypertension. Examples of chronic obstructive pulmonary diseases are asthma, bronchitis and emphysema; often these diseases occur in combination, generally bronchitis and emphysema are present together. Elevated pulmonary artery pressure can be an effect of any of these diseases. Contributing factors in the development of any chronic obstructive pulmonary disease include smoking, recurrent respiratory infections, air pollution and allergies.
Any cardiovascular abnormality, whether inherited or acquired, occurring in patients with an existing COPD, causes additional complications and increases the likelihood of increased pulmonary artery pressure which results in pulmonary hypertension. Pulmonary hypertension can occur in the absence of COPD, but as a result of a cardiac or pulmonary abnormality, either inherited or acquired. Pulmonary vasoconstriction caused by any factor, including disease or abnormalities of the pulmonary or cardiac system, can contribute to the development of secondary pulmonary hypertension.
The diverse range of mechanisms responsible for the development of secondary pulmonary hypertension means that no uniform approach to therapy is possible. Attention is focused on treatment of the underlying disease. The progressive nature of secondary pulmonary hypertension means that with time therapies become less effective in amelioration of the condition. The prognosis for patients with secondary pulmonary hypertension depends on the underlying disease and how successfully it can be treated.
Existing treatments include oxygen therapy to reduce hypoxemia and pulmonary vascular resistance, with strategies varying according to the underlying cause of the pulmonary hypertension. Methods of treatment of secondary pulmonary hypertension have been described previously (U.S. Pat. Nos. 5,028,628 and 5,554,610), with various substances being suggested as therapy for both primary and secondary pulmonary hypertension. Calcium channel antagonists and enzyme inhibitors have been used as treatments, and vasodilators such as hydralazine have been suggested for use in patients with primary pulmonary hypertension. Current therapies may serve to extend life expectancies of patients with secondary pulmonary hypertension but there is still a need for an improved treatment such as that which can be provided by the invention provided herein.
Vasoactive Intestinal Peptide
VIP is a basic, linear 28 amino acid polypeptide isolated initially from porcine duodenum (Mutt et al. (1974) Eur. J. Biochem. 42:581-589) and subsequently widely found in the central and peripheral nervous systems and in the digestive tract. VIP has strong vasodilating properties and hypotensive activity and systemic vasodilatory activity. Administered intravenously (IV) or directly into the heart, VIP increases heart rate and contractile force. Anderson et al. (1988) J. Cardio. Pharmacol. 12:365-371; Rigel et al. (1988) Am. J. Physiol. 255:H317-319; Karasawa et al. (1990) Eur. J. Pharmacol. 187:9-17; and Unverferth et al. (1985) J. Lab. Clin. Med. 106:542-550.
The amino acid structure of VIP was clarified in 1974, and since this structure is similar to both secretin and glucagon, VIP is considered to be a peptide hormone belonging to the glucagon-secretin family. Other members of this family of structurally related peptides include gastric inhibitory peptide (GIP), growth hormone releasing factor (GHRF) and adenylate cyclase-activating peptide (PACAP). Like all secretory peptides, VIP is derived by proteolytic cleavage from a larger precursor molecule. The 170 amino acid precursor preproVIP contains histidine isoleucine, another biologically active peptide. Itoh et al. (1983) Nature 304:547-549. VIP contains at least two functional regions: a region of receptor-specific binding and a region involved in biological activity. Oozes et al. (1989) Mol. Neurobiol. 3:201-236.
VIP mediates or modulates several basic cell functions. These include brain activity, endocrine functions, cardiac activity, respiration, digestion and sexual potency. The widespread physiologic distribution of VIP correlates with its involvement in a broad spectrum of biological activities. The actions of VIP are of a complex nature, encompassing receptor modulation, inducting release of neurotrophic factors, neurotransmission and neuromodulation. VIP occurs widely in the central and peripheral nervous systems and digestive tract, and may play a role in parasympathetic responses in the trachea and gastrointestinal tract.
VIP is an important modulator of cell growth, differentiation and survival during development of the sympathetic nervous system. VIP acts as a neuromodulator in several responses. Ferron et al. (1985) Proc. Natl. Acad. Sci. USA 82:8810-8812; and Kawatani et al. (1985) Science 229:879-881. In cholinergic studies VIP has a selective effect on muscarinic excitation in sympathetic ganglia with no apparent effect on nicotinic responses, indicating that VIP has intrinsic properties affecting electrical activity and also interacts with other neurotransmitter systems to modulate physiologic responses.
VIP has been found in glial cells and appears to be of physiological importance. VIP mediates communication between neurons and glia, a relationship of fundamental importance to neurodevelopment and function.
VIP immunoreactive fibers are present in and appear to be intrinsic to the canine heart. Weihe et al. (1981) Neurosci. Let. 26:283-288; and Weihe et al. (1984) Cell Tiss. Res. 236:527-540. VIP-containing neurons are present in canine hearts where VIP exerts a strong global myocardial effect similar to, but more sustained than, the adrenergic effect. The effect is qualitatively similar to other inotropic drugs that act through specific cell surface membrane receptors coupled to adenylate cyclase, for example β-adrenergic agonists such as proterenol.
VIP receptors are found in both canine and human hearts, thus canines are an appropriate model for VIP in humans. Vagal, efferent stimulation of β-blocked, atropinized dogs increased heart rate and contractile force, an effect that may be due to the release of VIP. Rigel et al. (1984) Am. J. Physiol. 246 (heart circ. physiol. 15) H168-173. VIP is released from dog atria when parasympathetic nerves are stimulated. Hill et al. (1993) J. Auton. Nerv. Sys. 43:117-122; and Hill et al. (1995).
Many different potential therapeutic uses of VIP, VIP analogues and VIP-like polypeptides have been proposed. Due to the widespread distribution and variety of activities of VIP, VIP, VIP analogues and VIP-like peptides have been proposed as treatment for various conditions including, among others, asthma and erectile dysfunction.
VIP is active when present in amounts of only picograms, and is stable in solution. This makes it particularly suited for use in a medicinal context.
VIP has inotropic and chronotropic effects due to its vasodilatory properties. Vasodilators cause vasodilation of or increased rate of blood flow through the arteries. Thus, upon administration of VIP, vasodilation or rate of blood flow would be expected to increase. VIP acts as a bronchodilator and a relaxant of pulmonary vascular smooth muscle.
The inotropic state of the ventricle may be affected by the activation of several receptors, some of which are coupled to adenylate cyclase. Foremost among these is the β-adrenergic receptor, which, when activated by its corresponding neurotransmitter norepinephrine, mediates increased cardiac contractility.
Additional positive inotropic cardiac receptor pathways have been identified although physiologic roles have not yet been established. These include pathways that respond to β-adrenergic agonists including histamine, serotonin, enkephalins and VIP. Of these, VIP is a potentially important agonist because it is present in nerve fibers in the heart, is coupled to adenylate cyclase, and, when administered IV, mediates both increased contractility and coronary vasodilation. There is some evidence that VIP has two discrete binding sites specific to the central nervous system.
The time-course of chronotropic effects of VIP is dose-dependent; however the time-course for recovery from inotropic effects is not. This may be due to variation in neurotransmitter levels in extracellular spaces, occurring due to heart movement. At a constant level of sympathetic nerve stimulation, dogs whose hearts were paced at different rates showed different recovery times from the inotropic response. Thus the recovery from VIP inotropic effects is affected by heart rate, which in turn is altered by the chronotropic effects. The inotropic and chronotropic effects of VIP are therefore related but do not occur through the same mechanism. There may be different receptors for the two responses or the biochemical cascade initiated differs for the two.
Intact endothelium is necessary to achieve vascular relaxation in response to acetylcholine. The endothelial layer modulates autonomic and hormonal effects on the contractility of blood vessels. In response to vasoactive stimuli, endothelial cells release short-lived vasodilators called endothelium-derived relaxing factor (EDRF) or endothelium-derived contracting factor. Endothelial cell-dependent mechanisms are important in a variety of vascular beds, including the coronary circulation.
The natural properties of VIP have been improved. The C-terminus holds a receptor recognition site, and the N-terminus holds the activation site with minimal binding capacity. These are essential to VIP function. Peptides non-essential to function have been manipulated and altered, resulting in some cases in increased levels of activity over natural VIP. These VIP analogues and VIP-like peptides can be utilized in any situation where VIP is effective. Some VIP analogues have improved storage properties and increased duration of action compared naturally occurring VIP, and therefore may be superior drugs. EP A 0613904; and U.S. Pat. Nos. 4,737,487; 5,428,015; and 5,521,157. VIP antagonists alter VIP function. U.S. Pat. No. 5,217,953.
VIP inervation has been demonstrated in the airways and pulmonary vessels (Dey et al. (1981) Cell Tiss. Res. 220:231-238), and the lungs are believed to be an important physiological target for VIP. The rat brain has VIP-specific receptor sites. (Taylor et al. (1979) Proc. Natl. Acad. Sci. USA 76:660-664) and guinea pig brain (Robberecht et al. (1978) Eur. J. Biochem. 90:147-154). The receptor-molecule complex has been identified in the intestine (Laburthe et al. (1984) Eur. J. Biochem. 139:181-187) and lung. Paul et al. (1985) Regul. Peptide 3:S52. Two classes of receptors with different pharmacological properties have been detected in rat lung (Patthi et al. (1988) J. Biol. Chem. 263:363-369), and in human colonic adenocarcinoma cells (El Baattari et al. (1988) J. Biol. Chem. 263:685-689).
cDNAs encoding rat (Ishihara et al. (1992) Neuron 8:811-819) and human (Sreedharan et al. (1993) Biochem. Biophys. Res. Comm. 193:546-553; and Sreedharan et al. (1995) Proc. Natl. Acad. Sci. USA 92:2939-2943) VIP receptors have been cloned; at least one of these receptors is structurally related to the secretin receptor. mRNA for this VIP receptor has been found in several tissues including liver, lung, intestine and brain. mRNA for another VIP receptor has been found in stomach, testes and brain.
The VIP receptor or receptors may be coupled to adenylate cyclase, as a VIP-stimulated adenylate cyclase has been identified in various areas of the central nervous system (Quick et al. (1978) Biochem. Pharmacol. 27:2209-2213 and Deschodt-Lanckman et al. (1977) FEBS Lett. 83:76-80), as well as the liver and pituitary (Rostene (1984) Progr. Neurobiol. 22:103-129). Studies of rat sensory neurons (Dobson et al. (1994) Neurosc. Lett. 167:19-23) show that VIP transcription may be increased via activation of cellular transcription factors that bind to a cyclic adenosine monophosphate (cAMP) responsive element. Tsukada et al. (1987) J. Biol. Chem. 262:8743-8747; and Giladi et al. (1990) Brain Res. Mol. Brain Res. 7:261-267.
VIP action on cAMP may be mediated via G-proteins, signal transducers that stimulate hydrolysis of GTP to GDP, as GTP and its analogues inhibit VIP-receptor binding and potentiate cAMP synthesis in response to VIP. Paul (1989) Biochem. Pharmacol. 38:699-702. If the VIP receptor is coupled to G-proteins, this could explain the array of VIP effects found, as G-proteins are widespread and involved in several signal transduction pathways. VIP induces its own mRNA in PC12 cells, probably as a result of its activation of adenylate cyclase. Tsukada et al. (1995) Mol. Cell. Endocrinol. 107:231-239. Regulation of VIP expression occurs also at a translational or post-translational level. Agoston et al. (1992). VIP may act as an autocrine regulator of its own synthesis.
VIP treatment produces a loss of responsiveness to subsequent rechallenges (Rosselin et al. (1988) Ann. NY Acad. Sci. 527:220-237); a short-term exposure to VIP results in internalization of the receptor-peptide complex (Boissard et al. (1986) Cancer Res. 46:4406-4413), a feature that may be tissue-specific (Anteunis et al. (1989) Am. J. Physiol. 256:G689-697). After internalization, VIP is degraded in lysosymes and may serve as an intracellular effector, while the receptors are recycled to the cell surface.
VIP binding sites and VIP-stimulated adenylate cyclase can be reduced by preincubation with different agents (Turner et al. (1988) J. Pharmacol. Exp. Ther. 247:417-423), although the different agents appear to function by different mechanisms. The VIP receptor appears to be translocated to a light vesicle fraction after such exposure. In some cell lines, the half-life of the receptor was around 2 days, and N-glycosylation was necessary for translocation. An internalized VIP receptor is dissociated from adenylate cyclase activity (Hejblum et al. (1988) Cancer Res. 48:6201-6210), although the internalization process is not completely independent of cAMP accumulation. VIP signal transduction thus relies on multiple pathways other than elevation of cAMP.
Thyroid Hormones
Infusion of thyroid hormones such as T4, T3, their analogues, derivatives and combinations thereof (hereinafter thyroid hormones) effectively resuscitates patients undergoing cardiac arrest. Rubin et al. U.S. Pat. No. 5,158,978. Thyroid hormones administered to patients with cardiovascular compromise are effective to restore or improve cardiac rhythm and function. Thyroid hormones are effective where standard treatments fail and are thus an improvement over standard treatments.
Thyroid hormones exert marked effects on the heart and peripheral circulatory system. Dillman et al. (1990) Am. J. Med. 88:626-630. Although the cardiovascular manifestation of hypo and hyperthyroidism has been known for over a century (Graves et al. (1835) Clinical Lectures, London Medical Surgical (part 2) 7:516-519), investigation of the therapeutic potential of thyroid hormone as a cardioactive agent is recent. Thyroid hormone can acutely affect myocardial performance. Novitsky et al. (1989) Eur. J. Cardio. Surg. 3:140-145.
Thyroid hormones include the L-forms of thyroxine (0-(4-Hydroxy-3,5-diiodophenyl)-3,5-diidotyrosine; T4) and 3,5,3′ triiodothyronine (triiodothyronine or T3). T3 is qualitatively similar to T4 in its biological effect but is more potent on a molar basis. Although some T3 is synthesized in the thyroid gland, the majority of naturally occurring T3 is synthesized by metabolism of T4 in peripheral tissues by the enzyme 5′ deiodinase.
Serum T3 is markedly decreased during cardiac arrest. Wortsman et al. (1987) Arch Intern. Med. 147:245-248. This study consisted of forty six patients, twenty four of whom had a cardiac arrest in the Intensive Care Unit (ICU), and twenty two patients in the control group, who were admitted to the ICU, but did not have a cardiac arrest. There were statistically significant differences between the two groups in regard to the thyroid function test. The cardiac arrest group had significantly lower T3 and elevated reverse T3 (rT3) during the arrest at zero minutes, and even further exaggerated differences at 10 minutes after arrest compared to the control group. The authors concluded that, “abnormalities on test measuring thyroid function are extremely common during cardiovascular emergency of cardiac arrest.” Wortsman et al. (1987).
In a recent study presented by Drs. Rubin and Ruffy at the 31st annual AAMI meeting, the authors' preliminary data showed thyroid hormone can successfully resuscitate during cardiac arrest. In an uncontrolled group of five dogs during cardiac arrest, despite the use of defibrillation and of standard drugs, CPR was unsuccessful. These animals were then administered large bolus doses of T4. All the animals were successfully resuscitated. A small controlled study was then undertaken. Four dogs were left in ventricular fibrillation for a period of seven minutes after which they were given 4 μg/kg of T3 IV bolus and defibrillated. Three out of four dogs were successfully resuscitated. Rubin et al. (1996) T3 in the use of Cardiac Resuscitation, 31st Annual Meeting of Association for the Advancement of Medical Instrumentation (AAMI), Philadelphia Pa. Previously, of dogs left in ventricular fibrillation for a period of 6 minutes, only 17% could be resuscitated. Skinner et al. (1971) Ann. Thor. Surg. 11:201-209. Therefore, in the control study, a time period of 7 minutes was used to allow the animals to remain in ventricular fibrillation before attempting CPR.
T3 regulates acute and chronic cardiac contractility. However, the mechanism is not well understood. Thyroid hormones (T3 and T4) and isoproterenol produce acute effects on the contractility of isolated rat hearts. Ririe et al. (1995) Anesthesiol. 82:1004-1012. The study also sought to determine whether the acute inotropic effects were mediated by a β-adrenergic receptor or by increased production of cAMP. The study demonstrated the following. T3 rapidly and significantly increased maximum dp/dt after a bolus injection. However, contractility following a maximum bolus of T4 remained unchanged. Isoproterenol also increased dp/dt, but onset of the action was significantly slower than T3 (peak action T3: 15 sec vs. 60 sec for isoproterenol). Also the actions of the acute inotropic effects of T3 were shown to be unrelated to the β-adrenergic receptor mechanisms or to generation of cAMP. Ririe et al. (1995). T3 in isolated rabbit ventricular myocytes acutely increased burst mode gating of Na+ channels. It was concluded that Na+ channel bursting may contribute to the acute positive inotropic effect of acute T3 administration in the stunned and ischemic myocardium. Dudley et al. (1993) Circ. Res. 73:301-313.
Thyroid hormone therapy for cardiovascular compromise includes but is not limited to adjunct therapy in any mechanical cardiac support system, EMD, post-cardiopulmonary bypass, cardiac arrest, cardiomyopathies and bradyarrhythmias. Adjunct therapy in any mechanical cardiac support system is useful to enhance heart function during and after support in situations including but not limited to cardiopulmonary bypass, ventricular assist device and intraaortic balloon.
Thyroid hormone treatment is indicated in EMD that is a result of post defibrillation and myocardial infarction and occurs when the electrical and physical actions of the heart become dissociated such that the electrical stimulation no longer produces a concomitant physical movement. Thyroid hormone treatment is useful in post-cardiopulmonary bypass when the attempt is made to restart the heart with epicardial defibrillation or when initial attempts are unsuccessful at restoring effective heart contraction.
Despite the many advances in the development of new drugs and devices for treating patients with cardiac arrest, these drugs and devices in the prior art have had little or no positive effect on the survival rate, which is still less than 10%. One reason for the low survival rate is that successful treatment depends upon determining the correct cause for abnormal cardiac contractions or lack of contractions.